Genetics-Chromosomal Abnormalities

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Wolf-
Hirschhorn syndrome

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the deletion of material from
the short arm of chromosome 4,

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Wolf-Hirschhorn syndrome facial appearance

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The eyes are set widely apart and
the nose is prominent

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Chromosomes condense into more compact structures during
cell division. Condensation begins in

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prophase when the nuclear
membrane disperses

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Chromosomes are most easily visualized at

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metaphase, when they are lined at the center of the cell.

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Down syndrome, a relatively common disorder characterized by

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facial appearance, decreased muscle tone, developmental
impairment and, sometimes, congenital malformation of the heart or
other organs

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individuals
with Down syndrome have 47 chromosomes, including

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an extra copy of
what appeared to be the smallest chromosome, designated 21.

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Turner syndrome

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Females
with short stature, lack of secondary sexual development, and infertility. have 45 chromosomes, including
only a single sex chromosome, an X

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Males with Klinefelter syndrome

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(male external genitals but slight breast development, tall stature, and
infertility) were found to have 47 chromosomes with an XXY karyotype.

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aneuploidy

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aneuploidy (a complete diploid set
of chromosomes with one or more extra or missing chromosomes

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Most common trisonomies

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Patau Syndrome Trysonomy 13
Edwards Syndrome Trysonomy 18
Down Syndrome Trisonomy 21

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Monosomy X is

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turner syndrome

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phytohemagglutinin,

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stimulate
the division of peripheral blood T lymphocytes

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colchicine

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inhibits the mitotic spindle accumulating cells at metaphase

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Metaphase chromosomes contain two strands

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chromatids, having replicated their genetic material at
interphase. The chromatids remain attached at the centromere, which
divides the most chromosomes into a short arm and a long arm.

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The
short arm is abbreviated

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for petit,

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long arm is abbreviated

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q (because it follows p.)

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The three largest were designated
group A. The first and third have their centromeres near the center and
are referred to as
The second has a centromere slightly
displaced from center and is called

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metacentric
submetacentric

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Group B consists
of two large chromosomes each with its centromere located

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toward the
end of the chromosome, also designated as submetacentric.

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Group C
includes seven pairs plus the X chromosome.Most members of this
group are

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submetacentric

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The three pairs of group D chromosomes
have centromere is near the end of the chromosome and are called

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acrocentric

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Group G contains two very small
acrocentrics, also with ribosomal DNA comprising substantial portions
of the short arms, and one of these is the

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extra chromosome of Down
syndrome. .

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The Y chromosome is a

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small submetacentric

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Q banded karyotype

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staining
with fluorescent dye quinacrine, was introduced because it was
hypothesized that variations of base sequence would exist along the
lengths of chromosomes and could be revealed by differential binding
of the alkylating agent quinacrine mustard, which reacts with G-C base
pairs.

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non-alkylating analog quinacrine dihydrochloride elicits

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bands of bright and dull fluorescence due to fluorescence enhancement
in AT-rich DNA and quenching in GC-rich regions.

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G banded karyotype

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pretreatment of chromosomes with a variety of agents (e.g., the
protease trypsin) followed by staining with Giemsa. The same bands
were seen as were elicited by quinacrine,

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most bright fluorescent bands
seen with

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quinacrine or darkly stained with Giemsa

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R banded karyotype

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Useful for defining chrosomes ends

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A pattern that is the reverse of
Q- or G-banding was produced with another staining technique
designated

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R-banding

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An approach to staining condensed
chromosome material near the centromeric regions was called

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Cbanding

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T-bands,
which stained

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the ends of chromosomes

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NOR staining, which
highlights

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the nucleolus organizer regions of the acrocentric
chromosomes.

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Histone octomer subunits

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H2A-H2B-H3-H4

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Giemsa light bands are rich in expressed sequences and high in GC content. Alu repeated sequences are

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GC rich and are found in or near expressed genes

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Giemsa dark band, have less expressed genes a high

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AT content

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what regions predominate in the Giemsa dark bands

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L1 repeated sequences which are rich in AT

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If chromosomes are studied early in mitosis before they are highly
compacted or if compaction is inhibited by treatment with a DNA
intercolating agents such as ethidium bromide..what can we see?

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very fine detail can be
discerned.

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The gain of an entire chromosome, such as occurs in Down syndrome,
is the result of

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nondisjunction. This involves missegregation of
chromosomes at meiosis or mitosis with two copies of a particular
chromosome going to one cell and no copy to the other cell.

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Embryos monosomic for an autosome usually do not survive. Most
autosomal trisomies are also nonviable, except for

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trisomies 13, 18, and
21.

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If non-disjunction occurs during mitosis in the developing embryo

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mosaicism results, wherein the embryo consists of a mixture of
trisomic and normal cells (again the monosomic cells usually die except
for monosomy X.)

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see

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pg 25 types of chromosomal anomalies

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A piece of a
chromosome may be lost

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results in monosomy

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lost by deletion or may be duplicated

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trisomy for
the genes

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Another intra-chromosomal rearrangement is formation of a
ring. This usually arises from breakage

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of the two ends and their
subsequent fusion into a ring structure.

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Translocations usually arise as reciprocal exchanges. If
no material is lost or gained the translocation is said to be

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balanced

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It is estimated that approximately 0.2% of
individuals carry and asymptomatic chromosomal rearrangement. If one
comes to medical attention, it is usually as a consequence of

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the
generation of unbalanced gametes during meiosis, leading to
spontaneous abortion or the birth of a child with congenital anomalies

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In the early days of
cytogenetics it was found that at the two ends of a chromosome there is
a sort of cap referred to as

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the telomere

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Breakage of the chromosome
leads to formation of a “sticky end,”which tends to be unstable. This is
avoided if

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the rearrangement involves exchange of material between
two chromosomes

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Reduction in telomerase activity has been hypothesized to be
responsible for

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the accumulation of chromosomal aberrations that
accompany cell senescence or malignancy.

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Balanced chromosomal rearrangements can spawn gametes with
genetic imbalance due to

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aberrant segregation during meiosis

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Meiosis
consists of two rounds of cell division and effects a reduction from

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the
diploid to haploid state in germ cells.

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Meiotic pairing between chromosomes involved in a balanced
translocation requires

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a complex association of four chromosomes: the
two involved in the exchange and the two homologs

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When the first
anaphase occurs these chromosomes can separate in several ways. If
the two normal homologs go to one cell and the two involved in the
exchange go to another, the resulting gametes will be genetically

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balanced: either normal or both having rearranged chromosomes

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Genetic imbalance will result if

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germ cells get one normal
chromosome and one rearranged chromosome

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The translocation
complex can also segregate so that three chromosomes go to one cell
and only one to the other. Rarely, all four chromosomes can go to the
same cell. Obviously

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major genetic imbalance results in these
instances.

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Translocations account for a minority of cases of

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Down syndrome

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Translocations between acrocentric chromosomes in which the long
arms fuse at the centromeres are referred to as

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Robertsonian
translocations.

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A Robertsonian translocation carrier has 45
chromosomes but is phenotypically normal. If, however, both the
translocated chromosome and a normal 21 go to the same germ cell at
meiosis, fertilization will result in

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trisomy 21.

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It is important to identify translocation cases because

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the
carrier is at risk of having additional offspring with trisomy

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Robertsonian
translocations Can be present in many members of a family, all of
whom are at risk of

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having children with Down syndrome

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Pairing between homologs where one chromosome is
inverted requires formation of a loop. Crossing over with in the loop
leads to duplication and efficiency of genetic material. If the inversion
does not include the centromere, called a

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paracentric inversion

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paracentric inversion lead to

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dicentric and acentric chromosomes result. These are usually unstable
at mitosis and lead to non-viable phenotypes

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Inversions that involve
the centromere, called pericentric inversions, lead to

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lead to partial trisomies
and monosomies, some of which may be viable.

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Visualization of chromosome structure requires access to dividing cells.
These can be obtained from the fetus by

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chorionic villus biopsy or
amniocentesis

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why is only the mother's age a factor in having a child with down syndrome

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in the male, meiosis begins after puberty and lasts only a few weeks. Continued mitotic division of spermatogonia may increase the rate of
gene mutation, but the rate of nondisjunction is lower than in oogenesis.

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When nondisjunction occurs during mitosis rather then meiosis the
result is

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chromosomal mosaicism

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Generally, Down syndrome due
to trisomy 21 mosaicism is indistinguishable from

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Downs syndrome in
general

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If trisomy 21 mosaicism is detected
prenatally or at birth, it is difficult to predict whether a full Down
syndrome phenotype will occur. The exact proportion of trisomy 21 cells
may differ from tissue to tissue. A low percentage of abnormal cells in
peripheral blood does not necessarily predict

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a low proportion in heart
or brain.

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Nonmosaic
trisomy, for most chromosomes, results in

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miscarriage during the first
trimester

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Trisomy 8 has been seen clinically only when

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it
is mosaic and as such produces a characteristic syndrome. In contrast,
complete trisomy 8 results in miscarriage.

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There is evidence that only a subset of genes on chromosome 21 is
responsible for the Down syndrome phenotype. Some individuals have
been found to have trisomy for only a small region of chromosome 21
due to

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segregation of an unbalanced translocation

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cytogenetic analysis under light microscope can only be done for

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sequences of more than a million bp

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DiGeorge Syndrome

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lack of para and thyroid glands has submicroscopic mutations. It shows no visual deletions under light microscopy

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Genomic Imprinting

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Some genes are not equally expressed from the maternal and paternal alleles. Rather either one of them is preferentially expressed at least during early development. . If the deleted allele is the one that it is mostly normally active, the gene will be absent even though one copy is retained

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The effects of imprinting first came to light in humans through studies of
rare individuals affected with cystic fibrosis who also had severe growth
and developmental delay. They were found to have inherited the cystic
fibrosis gene mutation, along with other genes on chromosome 7, from
just one parent. This is called

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uniparental disomy

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Uniparental disomy
is believed to be due to

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loss of one chromosome in a trisomic
conceptus

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Trisomy 7 would be nonviable, but if in early development one of the
three copies of chromosome 7 in a trisomic embryo is lost by
disjunction,

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the normal number of chromosomes would be restored. If
the remaining copies of chromosome 7 are derived from the same
parent, however, uniparental disomy results, which will have phenotypic
consequences if the chromosome includes imprinted genes.

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Prader Willi and Angelmann syndromes are associated with

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deletions of same region of chromosome 15

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Phenotype of chromosome 15 region is
If maternal sequences are deleted

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Prader Willi
Angelmann

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In some cases of Prader willi-Angelmann syndrome, no deletions occur but instead there is

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uniparental disomy for the paternal (giving Angelmann) or for the maternal (giving prader)

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fragile X syndrome

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The fragile
X site is seen only if the cells are grown in culture medium that is
deficient in thymidine and folic acid, or in medium supplemented with
fluorodeoxyuridine, an inhibitor of thymidylate synthetase.

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Depletion of
nucleotide pools stimulates the expression of

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fragile sites such as
fragile X. There are other folate-sensitive fragile sites in the human
genome, but fragile X is the only one associated with a phenotype.

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Not all cells of a male with fragile X syndrome display

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the fragile X
chromosome (5-50%)

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Fragile X syndrome offspring carrier percentage

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50% of the male offspring and 30% of the female offspring of a carrier
mother will develop fragile X syndrome

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The
cytogenetic test for fragile X is not as reliable for

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females as for males,
however. A positive test in a female is significant, but many female
carriers for fragile X have normal cytogenetic studies.

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males appear to be obligate carriers but do not themselves
manifest signs of the condition The phenomenon of nonmanifesting
males is called the

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Sherman paradox.